Induction of heat shock proteins (Hsps), a class of molecular chaperones, is a physiological and biochemical response to abrupt increases in temperature or exposure to a variety of other metabolic insults, including heavy metals, amino acid analogs, toxins, and oxidative stress. This response occurs in all prokaryotic and eukaryotic cells and is characterized by repression of normal protein synthesis and initiation of transcription of Hsp-encoding genes. Under normal or nonstressed conditions, constitutively expressed Hsps facilitate proper protein folding and maturation, promote protein translocation across membranes, and regulate hormone receptor and protein kinase activity (Hightower, L. E. et al. (1991) Cell, 66: 191-197).
Hsps function by associating with cellular proteins and regulating their conformation. The conformational properties of a protein are determinants of protein activity, aggregation, degradation, and function. Hsp70s act by maintaining proteins in an unfolded conformation, while the Hsp60/GroEL complexes act by facilitating protein folding. Hsp90s act in a maturational or regulatory capacity on specific molecules including steroid hormone receptors; the small Hsps (20 kDa to 30 kDa) are able to suppress aggregation and heat inactivation of various proteins, including actin (Hickey, E. et al. (1986) Nucleic Acids Res. 14: 4127-4145; and Miron, T. et al. (1991) J. Cell Biol. 114: 255-261).
Overexpression of Hsps in transgenic mice and rats or prior heat exposure of normal animals to induce Hsps protects the heart muscle from ischemic injury. Both heat shock-induced and exogenous Hsps protect smooth muscle cells from serum deprivation-induced cell death. Overexpression of Hsps also protects murine fibroblasts from both UV light injury and proinflammatory cytokines released during UV exposure (Marber, M. S. et al. (1995) J. Clin. Invest. 95: 1446-1456; Simon, M. M. et al. (1995) J. Clin. Invest. 95: 926-933).
Hsps are located in all major cellular compartments and function as monomers, multimers, or complexed with other cellular proteins. Hsps bind to steroid hormone receptors, repress transcription in the absence of the ligand, and provide the proper folding of the ligand-binding domain in the presence of the hormone. Specific Hsps bind immunosuppressive drugs and may play a role in modulation of immune responses. Hsps expressed in cancer cells can protect the cancer cells from the cytotoxic effects of drugs used in anticancer therapies. Hsps isolated from tumor cells, when purified and used as an antigen, have been shown to provide immunity to the tumors from which they are isolated (Udono, H. et al. (1994) J. Immunol. 152: 5398-5403; Fang, Y. et al. (1996) J. Biol. Chem. 271: 28697-28702; and Young R. A. (1990) Annu. Rev. Immunol. 8: 401-420).
Several of the constitutive Hsp genes are located in the major histocompatibility complex on chromosome 6, and members of the Hsp family play roles in T-cell mediated regulation of inflammation and immune recognition. Heat shock treatment of B-cells enhances processing of antigen and the assembly and function of MHC class II molecules (Sargent, C. A. et al. (1989) Proc. Natl. Acad. Sci. 86: 1968-1972; Hendrick, J. P. et al. (1993) Proc. Natl. Acad. Sci. 90: 10216-10220).
Knockout mice are providing additional information on the roles of Hsps. For example, female homozygous knockout mice for Hsp70 are found to undergo normal meiosis and are fertile. In contrast, the male homozygous knockout mice lack postmeiotic spermatids and mature sperm and are infertile (Dix, D. J. et al. (1996) Proc. Nat. Acad. Sci. 93: 3264-3268).
The discovery of a new heat shock-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and immune disorders.